Retinol derivative and cosmetic composition comprising the same

ABSTRACT

The present invention relates to a novel retinol derivative and a cosmetic composition comprising the same, in particular, to a novel retinol derivative represented by the formula (I) exhibiting the effects from both L-ascorbic acid and retinol as well as being free from the disadvantages of two compounds such as skin irritation and instability in cosmetic formulation, and a cosmetic composition comprising the retinol derivative. (I)

This application is the US national phase of international applicationPCT/KR02/02383 filed 18 Dec. 2002, which designated the US. The entirecontents of this application is incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel retinol derivative and acosmetic composition comprising the same, in particular, to a novelretinol derivative exhibiting the effects from both L-ascorbic acid andretinol as well as being free from the disadvantages of two compoundssuch as skin irritation and instability in cosmetic formulation, and acosmetic composition comprising the retinol derivative.

2. Description of the Related Art

Various reasons may lead to skin spots such as freckles. The main reasonis ultraviolet radiation. When skin is exposed to ultraviolet ray,melanin is generated in melanocytes and released and deposited onepidermis, resulting in formation of skin spots such as freckles. In theprocess of melanin generation in melanocytes, tyrosinase catalyzes theformation of DOPAquinone using tyrosine as substrate and thenDOPAquinone undergoes spontaneous reaction and enzyme reaction togenerate a copolymeric black pigment, melanin. Thus, to maintain a clearand fair skin, it is necessary to inhibit melanin biosynthesis inmelanocytes and the deposition of melanin on skin.

L-ascorbic acid (Vitamin C) exerts good antioxidizing property,inhibition of melanin biosynthesis in melanocytes and enhancement ofcollagen biosynthesis in fibroblast, so that it is generally used asactive ingredient in cosmetics for whitening skin color or eliminatingwrinkle. However, L-ascorbic acid has a limitation as cosmetic materialdue to instability in cosmetic formulation. In order to overcome suchdisadvantage, several derivatives, which include AA-2P (L-ascorbic acid2-phosphate), AA-2S (L-ascorbic acid 2-sulfate), AA-6G(6-O-α-D-glucopyranosyl-L-ascorbic acid) and AA-2G(2-O-α-D-glucopyranosyl-L-ascorbic acid), have been developed andemployed in place of L-ascorbic acid as cosmetic ingredient.

Skin aging is ascribed to intrinsic aging and photo aging and the latteris believed to a main factor for skin aging. Photo aging is likely to bea cumulative result of the changes occurring in skin such as wrinkles,thickening, flaccidity, decreased elasticity, roughness, dryness andspots, which are attributed to aging by sunlight, in particular,ultraviolet. In other words, skin aging by sunlight may cause thechanges in epidermis and dermis, thereby giving rise to wrinkles,thickening and decreased elasticity of skin.

Retinol (Vitamin A) has been well known as cosmetic material fortreating and preventing skin aging (U.S. Pat. Nos. 4,603,146 and4,877,805). Retinoid useful for skin caring includes retinol (vitamin Aalcohol), retinal (vitamin A aldehyde) and retinyl acetate, retinylpropionate, retinyl linoleate and retinyl palmitate as retinyl esters.Among them, retinol found in human cell is pivotal in differentiationand growth of epithelial tissue and exhibits higher stability than otherretinoids, which enable popular employment of retinol as cosmeticmaterial. However, retinol having the superior effects in treatment andprevention of wrinkle and acne has some disadvantages: (a) asformulated, the changes of color and odor and the reduced efficacy; and(b) skin irritation while low level of retinol is used. Therefore, theuse of retinol as cosmetic material has been highly limited.

SUMMARY OF THE INVENTION

Endeavoring to develop novel compound exhibiting synergic effect ofL-ascorbic acid and retinol as well as being free from the disadvantagesof the two compounds, the present inventors have developed novel retinolderivative exhibiting better whitening effect and treating andpreventing effect of wrinkle than L-ascorbic acid and retinol as well ashighly decreased irritation and better stability in cosmeticformulation.

Accordingly, it is an object of this invention to provide a novelretinol derivative.

It is another object of this invention to provide a cosmetic compositioncomprising the retinol derivative as active ingredient.

Other objects and advantages of the present invention will becomeapparent from the detailed description to follow taken in conjugationwith the appended claims and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing improved whitening effect of the presentretinol derivative. Alphabets on x-axis denote the formulations of TableI.

DETAILED DESCRIPTION OF THIS INVENTION

In one aspect of this invention, there is provided a retinol derivativerepresented by the following formula (I):

L-ascorbic acid (Vitamin C) is known to have antioxidizing activity,inhibition of melanin biosynthesis in melanocytes (whitening effect) andenhancement of collagen biosynthesis (treating and preventing wrinkle).However, L-ascorbic acid has a limitation as cosmetic material duemainly to instability in cosmetic formulation. Retinol capable ofpromoting the differentiation and growth of epithelial tissue is knownto have the superior effect in treatment and prevention of wrinkle.However, in cosmetic formulation, the color and odor of retinol are verylikely to be changed and the efficacy of retinol is likely to bereduced. In addition, as applied to skin, retinol is apt to induceirritation. Therefore, the use of retinol is considerably restricted incosmetic composition.

The present inventors have made intensive studies to develop a novelcompound exhibiting better efficacy than L-ascorbic acid and retinol aswell as being free from the shortcomings previously described.

In the novel retinol derivative of this invention, L-ascorbic acid islinked to carbon-15 of retinol through a diester bond rather than directlinkage. Hydroxyl group of carbon-3 of L-ascorbic acid is involved inthe linkage to retinol, which is one of structural features of thisretinol derivative. While L-ascorbic acid has several reactive hydroxylgroups, only hydroxyl group of carbon-3 is involved in the linkage toretinol in the present retinol derivative. This is because that thehydroxyl group of carbon-3 of L-ascorbic acid is the most reactive groupand the hydroxyl group of carbon-2 plays a very important role inexhibiting an activity of L-ascorbic acid.

The present derivative is prepared through (a) esterification of retinoland (b) reaction between esterified retinol and L-ascorbic acid. Oneexample of preparing method for the present derivative is as follows:

-   (1) Esterification of Retinol with Bromo Acetic Acid

-   (2) Reaction between Esterified Retinol and L-Ascorbic Acid

The novel retinol derivative of this invention is found to exhibitbetter efficacies (e.g. enhancement of collagen biosynthesis, inhibitionof melanin generation and antioxidation) than L-ascorbic acid andretinol as well as to overcome the shortcomings of the compounds (e.g.instability in formulation and induction of skin irritation).

Therefore, the novel retinol derivative of this invention can be used asactive ingredient in cosmetic composition for skin whitening and/or skincaring (e.g. treating and preventing wrinkles).

In another aspect of this invention, there is provided a cosmeticcomposition comprising: (a) a cosmetically effective amount of a retinolderivative represented by the following formula (I); and (b) acosmetically acceptable carrier:

Since the present composition employs the retinol derivative representedby the formula (I) as active ingredient, the common descriptions betweenthem are omitted in order to avoid the complexity of this specificationleading to undue multiplicity.

The cosmetic composition of this invention represents a variety ofefficacies including enhancement of collagen biosynthesis,antioxidation, inhibition of tyrosinase activity, inhibition of melaningeneration, skin whitening, and treatment and prevention of wrinkle,which are ascribed to the retinol derivative represented by the formula(I). These efficacies are found to be better than those of L-ascorbicacid and retinol.

Preferably, the amount of the retinol derivative ranges from 0.0001 to10.0 wt % based on the total weight of the composition. If the amount ofthe retinol derivative is lower than 0.0001, the efficacies originatedfrom the derivative may be negligible; in the case of exceeding 10.0 wt%, the efficacies of retinol derivative in parallel with the increase ofamount may be rarely represented and the side effects such as inductionof skin irritation and instability in formulation may be becomeapparent. Therefore, it is more advantageous that the amount of theretinol derivative is in the range of 0.0005 to 10.0 wt %, morepreferably, 0.05 to 10.0 wt % and most preferably, 1.0 to 3.0 wt % basedon the total weight of the composition. The present compositioncomprising the most preferable amount of the retinol derivative is foundto exert much better efficacies than L-ascorbic acid and retinol and tobe completely free from the shortcomings of the conventional compounds.

The cosmetic compositions of this invention may be formulated in a widevariety of forms, for example, including a solution, a suspension, anemulsion, a paste, an ointment, a gel, a cream, a lotion, a powder, asoap, a surfactant-containing cleanser, an oil, a powder foundation, anemulsion foundation, a wax foundation and a spray.

The cosmetically acceptable carrier contained in the present cosmeticcomposition, may be varied depending on the type of the formulation. Forexample, the formulation of ointment, pastes, creams or gels maycomprise animal and vegetable fats, waxes, paraffins, starch,tragacanth, cellulose derivatives, polyethylene glycols, silicones,bentonites, silica, talc, zinc oxide or mixtures of these substances. Inthe formulation of powder or spray, it may comprise lactose, talc,silica, aluminum hydroxide, calcium silicate, polyamide powder andmixtures of these substances. Spray may additionally comprise thecustomary propellants, for example, chlorofluorohydrocarbons,propane/butane or dimethyl ether.

The formulation of solution and emulsion may comprise solvent,solubilizer and emulsifier, for example water, ethanol, isopropanol,ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,propylene glycol, 1,3-butylglycol, oils, in particular cottonseed oil,groundnut oil, maize germ oil, olive oil, castor oil and sesame seedoil, glycerol fatty esters, polyethylene glycol and fatty acid esters ofsorbitan or mixtures of these substances. The formulation of suspensionmay comprise liquid diluents, for example water, ethanol or propyleneglycol, suspending agents, for example ethoxylated isosteary alcohols,polyoxyethylene sorbitol esters and poly oxyethylene sorbitan esters,micocrystalline cellulose, aluminum metahydroxide, bentonite, agar andtragacanth or mixtures of these substances.

The formulation of soap may comprise alkali metal salts of fatty acids,salts of fatty acid hemiesters, fatty acid protein hydrolyzates,isethionates, lanolin, fatty alcohol, vegetable oil, glycerol, sugars ormixtures of these substances.

Furthermore, the cosmetic compositions of this invention may containauxiliaries as well as carrier. The non-limiting examples of auxiliariesinclude preservatives, antioxidants, stabilizers, solubilizers,vitamins, colorants, odor improvers or mixtures of these substances

The compositions of this invention are significantly effective inwhitening and caring (treating and preventing wrinkles) skin originatedfrom the retinol derivative of the formula (I).

The following specific examples are intended to be illustrative of theinvention and should not be construed as limiting the scope of theinvention as defined by appended claims.

EXAMPLE Synthesis of Retinol Derivative

In a reactor, bromo acetic acid and 1,3-dicyclohexylcarbodiimide (DCC)were added to retinol (Sigma-Aldrich) dissolved in chloroform and acatalytic amount of 4-dimethylaminopyridine was added, followed bystirring. After completion of reaction, the resultant was filtered,extracted with chloroform and dried over anhydrous magnesium sulfate,followed by filtration and concentration, thus yielding bromo aceticacid retinol ester as oil in yellow color.

L-ascorbic acid (Sigma-Aldrich) were dissolved in of DMSO and ofpotassium bicarbonate were added, followed by stirring. To the resultantwas added bromo acetic acid retinol ester. Upon the completion of thereaction, the mixture was extracted with ethyl acetate and dried overanhydrous magnesium sulfate, followed by filtration and concentration toyield final product as oil in brown color: Anal. Caclc. For C₂₈H₃₈O₈(502.60): C 66.91; H 7.62; O 25.47: found C 67.12; H 7.54; O 25.34

Formulation Example

The cosmetic compositions were made as described in Table I.

TABLE I Ingredient Form. A Form. B Form. C Form. D Form. E Derivative**2.0* — — 0.05 10.0 Retinol — 2.0 — — — L-ascorbic acid — — 2.0 — —Propylene 6.0 6.0 6.0 6.0 6.0 glycol Glycerine 4.0 4.0 4.0 4.0 4.0Triethanol 1.2 1.2 1.2 1.2 1.2 amine Tocopheryl 3.0 3.0 3.0 3.0 3.0acetate Liquid paraffin 5.0 5.0 5.0 5.0 5.0 Squalane 3.0 3.0 3.0 3.0 3.0Makadamianut 2.0 2.0 2.0 2.0 2.0 oil Polysorbate 60 1.5 1.5 1.5 1.5 1.5Sorbitan 1.0 1.0 1.0 1.0 1.0 sesquinoleate Propyl paraben 0.1 0.1 0.10.1 0.1 Carboxyvinyl 1.0 1.0 1.0 1.0 1.0 polymer Pf. Kn-921 0.3 0.3 0.30.3 0.3 Distilled water Residual Resid- Residual Residual Residualamount ual amount amount amount amount Total 100 100 100 100 100*expressed as weight percentage **the retinol derivative of thisinvention

Experimental Example I Evaluation of Effect on Collagen Biosynthesis

Human normal fibroblasts (ATCC) were inoculated (2×10⁴ cells/well) on96-well microplate containing DMEM supplemented with FBS and incubatedfor 24 hours at 37° C. After incubation, the medium in microplate wasreplaced with fresh DMEM without serum comprising the derivative of thisinvention, retinol or ascorbic acid and then additional incubation for48 hours was carried out. Control was not treated with any of thecompounds described above. Following incubation, each well was rinsed,fresh DMEM without serum was supplied and then additional incubation for24 hours was performed. Then, procollagen type C-peptide obtained fromthe supernatant of each well was measured using a kit purchased fromTakara Co. (Japan) and the measured values were converted to ng/2×10⁴cells, which indicate the amount of collagen newly generated. Theresults are summarized in Table II.

TABLE II Amount of Collagen Newly Generated (ng/2 × 10⁴ cells) AdditionL-ascorbic Amount acid Retinol Derivative Control*  50 μg 198 174 215 75100 μg 267 233 290 68 200 μg 314 286 349 79

As indicated in Table II, it was found that the retinol derivative ofthis invention is much more effective than retinol and ascorbic acid incollagen biosynthesis of human fibroblast. In addition, the retinolderivative of this invention was found to exhibit the effect ofenhancing collagen biosynthis in a dose dependent manner.

Experimental Example II Evaluation of Scavenging Effect on Free Radical

Evaluation of scavenging effect on free radical was performed using DPPH(1,1-diphenyl-2-picryl-hydrazyl, Sigma-Aldrich). 100 μl of each of thesubstances (the derivative of this invention, retinol and ascorbic acid)diluted to a suitable concentration and 100 μl of 400 μM DPPH solutionwere consequently added to a 96-well microplate and agitation wasperformed, followed by reaction for 30 min. at room temperature. Then,absorbance at 520 nm was measured using spectrophotometer. Controlcontains 100 μl of ethanol in place of the substance to be tested. Thescavenging effect on free radical was calculated as following formula:scavenging effect on free radical (%)=100−{(absorbance of samplesolution/absorbance of control)×100}

The results are summarized in Table III.

TABLE III Substance to be Scavenging effect tested Concentration on freeradical (%) Derivative of this 0.5 mM 95.7 invention   1 mM 96.4 Retinol0.5 mM 0.4   1 mM 1.6 L-ascorbic acid 0.5 mM 91.2   1 mM 91.9

As shown in Table III, the present derivative was found to exhibitimproved scavenging effect on free radical compared to L-ascorbic acid.

Experimental Example III Evaluation of Inhibitory Effect on TyrosinaseActivity

A tyrosinase used herein was purchased from Sigma (U.S.A.). Tyrosine assubstrate was used as a solution (0.1 mg/ml) dissolved in 0.05 M sodiumphosphate buffer (pH 6.8).

0.5 ml of tyrosine solution was placed in a test tube and 0.5 ml ofsample solution to be evaluated was added. The test tube was allowed tostand in incubator for 10 min. at 37° C. and then 0.5 ml of tyrosinase(200 U/ml) was added. The reaction was carried out for 10 min at 37° C.As a control group, 0.5 ml of buffer solution was added instead of thesample to be evaluated. The reaction was quenched by placing the testtube on ice and the absorbance of the resultant was measured at 475 nmwith spectrophotometer. The inhibitory effect on tyrosinase activity wasdetermined by the equation: inhibition rate on tyrosinase activity(%)=100−{(absorbance of sample/absorbance of control)×100}

The results are shown in Table IV.

TABLE IV Inhibition rate on tyrosinase activity (%) Sample Conc.Derivative of (μg/ml) L-ascorbic acid Retinol this invention 10 5.1%0.6% 8.1% 20 9.8% 1.1% 10.7% 50 13.2% 3.2% 13.8% 100 22.5% 3.9% 32.9%200 34.8% 5.6% 47.1% 500 62.4% 9.2% 78.8%

As indicated in Table IV, the derivative of this invention was found toshow higher inhibition rate on tyrosinase activity than ascorbic acid.Therefore, it will be appreciated that the inhibitory effect on melaninformation of the present derivative is higher than that of ascorbicacid.

Experimental Example IV Evaluation of Whitening Effect

Whitening effect of the present derivative was evaluated throughpractical use test. Test group aged 19-40 consisted of thirty women whoshowed relatively dark skin. Measurement of whitening effect wasperformed at an interval of 2 weeks using Minolta CR 300 for 8 weeks.Each of the formulations described in Table I (Formulations A-E) wasapplied to each of 5 portions (1×1 cm) of forearm. The results arerepresented in FIG. 1.

As shown in FIG. 1, the formulations comprising the present derivative(Form. A, D and E) represent much higher □L value than control group andthe formulations A and E are revealed to show higher □L value thanL-ascorbic acid. Therefore, it is known that the present derivative hasimproved whitening effect compared to L-ascorbic acid.

Experimental Example V Evaluation of Skin Irritation

In order to confirm whether the formulations described in Table I (Form.A-E) induce a skin irritation, the test was carried out. Test groupconsisted of fifty healthy adults. Each of the formulations (about 0.1g) as patch form was applied to a portion (5×20 cm) in forearm of testeefor 24 hours and then removed. After 1 hour and 24 hours, a skincondition was evaluated with naked eye, of which results are indicatedin Table V. In Table V, the skin condition was evaluated as thefollowing criteria: “−”: not observing particular symptoms such aserythema; “+−”: becoming slightly reddish; “+”: becoming significantlyreddish; and “++”: becoming severely reddish and swollen.

In Table V, the irritation rates was calculated as the followingequation: irritation rate={[No. of (+−)×1+No. of (+)×2+No. of(++)×3]/[No. of testee×3]}×100

TABLE V No. of Evaluation Result Irritation Formulation testee ++ + +− −Rate (%) A 50 − − 2 48 1.3 B 50 − − 3 47 2.0 C 50 − − 2 48 1.3 D 50 − −1 49 0.7 E 50 − 1 4 45 4.0

As known in Table V, the formulation A comprising the present derivativeshows relatively low irritation rate compared to other formulations. Itis notable that the formulation A exhibits much lower irritation ratethan the formulation B comprising retinol.

Experimental Example VI Evaluation of Wrinkle Treatment

Forty-five women aged above 30 (mean age 33.7) were classified to 3groups. To group A, was applied the formulation A, to group B theformulation B and to group C the formulation D. Applied portion was eyerims with wrinkles and the time period for application was 12 weeks.After application, the objective evaluation was made by well-trainedtester and the subjective evaluation was made by testee oneself. Theevaluation of wrinkle treatment was made according to 7 levels rangingfrom −3 (showing very severe deterioration of wrinkle) to 3 (showingremarkable amelioration of wrinkle). The results are summarized inTables VI and VII.

TABLE VI Objective Evaluation of Wrinkle Treatment Level of WrinkleTreatment A B D Testee 0 day* 12 wk** 0 day 12 wk 0 day 12 wk Testee 1 03 0 3 0 2 Testee 2 0 2 0 3 0 3 Testee 3 0 3 0 2 0 2 Testee 4 0 3 0 3 0 2Testee 5 0 3 0 3 0 3 Testee 6 0 3 0 3 0 3 Testee 7 0 3 0 2 0 3 Testee 80 2 0 2 0 2 Testee 9 0 2 0 3 0 2 Testee 10 0 3 0 3 0 3 Testee 11 0 3 0 20 2 Testee 12 0 3 0 3 0 2 Testee 13 0 3 0 3 0 2 Testee 14 0 3 0 3 0 3Testee 15 0 2 0 2 0 3 Mean 0 2.73 0 2.67 0 2.47 *level of wrinkletreatment at the beginning time of the test **level of wrinkle treatmentafter 12 weeks from the test

TABLE VII Subjective Evaluation of Wrinkle Treatment Level of WrinkleTreatment A B D Testee 0 day* 12 wk** 0 day 12 wk 0 day 12 wk Testee 1 03 0 2 0 3 Testee 2 0 2 0 3 0 2 Testee 3 0 3 0 3 0 2 Testee 4 0 3 0 3 0 3Testee 5 0 3 0 3 0 3 Testee 6 0 3 0 2 0 3 Testee 7 0 3 0 3 0 2 Testee 80 2 0 2 0 3 Testee 9 0 2 0 3 0 3 Testee 10 0 3 0 3 0 2 Testee 11 0 3 0 20 2 Testee 12 0 3 0 2 0 3 Testee 13 0 3 0 3 0 2 Testee 14 0 3 0 3 0 3Testee 15 0 2 0 3 0 2 Mean 0 2.73 0 2.67 0 2.53 *level of wrinkletreatment at the beginning time of the test **level of wrinkle treatmentafter 12 weeks from the test

As known in Tables VI and VII, the formulation A containing the presentderivative was found to exhibit improved effect on wrinkle treatment,which showed 2.67 and 2.73 in objective and subjective evaluations,respectively.

Experimental Example VII Evaluation of Formulation Stability

The formulations A, B, C, D and E described in Table I were stored in anopaque container for 12 weeks with keeping constant temperature. Then,the separation and the discoloration levels of the formulations weremeasured. The separation and the discoloration levels were classified to6 levels: 0: no change; 1: very slightly discolored (separated); 2:slightly discolored (separated); 3: slightly remarkable discoloration(separated); 4: remarkable discoloration (separated); and 5: veryremarkable discoloration (separated)

TABLE VIII Discoloration (Separation) Level Temp. A B C D E 45° C. 0 1 00 1  4° C. 0 0 0 0 0

As indicated in Table VIII, it was found that the formulation Acontaining the present derivative is more stable than the formulation Bcontaining retinol. The formulations containing the present derivativewas revealed to show a slight discoloration, if the amount of thepresent derivative is more than 10 wt %.

Having described a preferred embodiment of the present invention, it isto be understood that variants and modifications thereof falling withinthe spirit of the invention may become apparent to those skilled in thisart, and the scope of this invention is to be determined by appendedclaims and their equivalents.

1. A retinol derivative represented by the following formula (I):


2. A cosmetic composition comprising: (a) a cosmetically effectiveamount of a retinol derivative represented by the following formula (I);and (b) a cosmetically acceptable carrier:


3. The cosmetic composition according to claim 2, wherein thecomposition has an effect selected from the group consisting ofenhancement of collagen biosynthesis, antioxidation, inhibition oftyrosinase activity, skin whitening, treatment of wrinkles andcombinations thereof.
 4. The cosmetic composition according to claim 2,wherein the retinol derivative is present in an amount of 0.0001-10.0 wt% based on the total weight of the composition.
 5. The cosmeticcomposition according to claim 4, wherein the retinol derivative ispresent in an amount of 1.0-3.0 wt % based on the total weight of thecomposition.
 6. The cosmetic composition according to claim 2, whereinthe cosmetic composition is in the form of one selected from the groupconsisting of a solution, a suspension, an emulsion, a paste, anointment, a gel, a cream, a lotion, a powder, a soap, asurfactant-containing cleanser, an oil, a powder foundation, an emulsionfoundation, a wax foundation and a spray.